Prostaglandins are a class of physiologically active substances which are derived from eicosapolyenoic acid such as arachidonic acid through biosynthetic pathway in animal tissues and have, as a fundamental chemical structure, prostanoic acid of the formula: ##STR4##
Prostaglandins are produced through biosynthesis in various tissues, and classified into several families Thus, prostaglandins are categorized into A-J groups depending on the position of oxgen atom attached to the 5 membered ring moiety and the position of a double bond in the ring moiety. Alternatively, prostaglandins can be categorized into 3 groups depending on the number of double bonds in the side chains. As a result, prostaglandins are designated as PGA.sub.2, PGE.sub.1, PGF.sub.2.alpha., according to both categorizations.
Prostaglandins possess as a whole diverse bioactivities, which include, for example, vasodilator activity, platlet aggregation-inhibiting activity, uterotonic activity, gastrointestinal motility-promoting activity, etc.
Further, some prostaglandins have intraocular pressure-reducing activity. For example, Japanese Patent Publication (kokai) No. 1418/1984 describes that PGF2.alpha. has a high intraocular pressure-reducing activity and that 15-keto-PGF.sub.2.alpha. has the same activity although it is less potent. However, these natural prostaglandins are chemically and biologically labile, and are easily subject to metabolic degradation because they contain in the chemical structure a labile allyl alcohol moiety comprising a double bond between 13 and 14 positions and a hydroxy group at 15 position in the .omega. chain.
13,14-Dihydro-15-ketoprostaglandin which is a metabolic product of prostaglandins has been known as a compound which does not contain the labile moiety and has been known to be a useful compound having the intraocular pressure-reducing activity.
The inventors of the invention have found new useful compounds by screening a large amount of prostaglandin derivatives which are stable and capable of being chemically synthesized. Also, the inventors of the invention found that derivatives of conventional prostaglandins which are derived from said conventional prostaglandins by deleting the hydroxy group at 15-position are more stable, particularly in liquid phase, than the conventional prostaglandins, and that they show the intraocular pressure-reducing activity. Thus, the invention provides a new use of these derivatives. In particular, the compounds as described below have a significant intraocular pressure-reducing activity, while they do not produce any side effects such as hyperemia of conjunctiva, and initial increase in intraocular pressure which are often observed in known prostaglandins. Accordingly, the 15-deoxyprostaglandins may be a therapeutical agent useful for treating an ocular disease, in particular glaucoma, which is assumed to be caused by increased intaocular pressure.
As one embodimet, the present invention provides a method for treating hypertension or glaucoma in the eye comprising contacting the surface of the eye with a therapeutic amount of a 15-deoxyprostaglandin derivative of the formula (I): ##STR5## in which ##STR6## is a 5 membered ring which is selected from a group consisting of ##STR7## R.sup.1 is hydrogen or lower alkyl; R.sup.2 is C.sub.6 -C.sub.12 alkyl, C.sub.6 -C.sub.12 alkenyl or C.sub.6 -C.sub.12 alkadienyl or a pharmaceutically acceptable salt thereof.
The term "C.sub.6 -C.sub.12 alkyl" in the definition of R.sup.2 refers to hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl. R.sup.2 may be an unsaturated haydrocarbon chain containing one or more double bonds, with C.sub.8 -C.sub.10 alkenyl or C.sub.8 -C.sub.10 alkadienyl being preferred. Specific examples of the unsaturated hydrocarbon chain are 1-hexenyl, 2-hexenyl, 1,3-hexadienyl, 1-heptenyl, 2-heptenyl, 1,3-heptadienyl, 1-octenyl, 2-octenyl, 1,3-octadienyl, 1-nonenyl, 2-nonenyl, 1,3-nonadienyl, 1-decenyl, 2-decenyl, 1,3-decadienyl, 1-undecenyl, 2-undecenyl, 1,3-undecadienyl, 1-dodecenyl, 2-dodecenyl, and 1,3-dodecadienyl.
15-Deoxyprostaglandin derivatives of the formula (I) include all of the stereoisomers and mixture thereof.
Preferably, 15-deoxyprostaglandin derivatives of the above formula in which ##STR8## are used in the method of the present invention. More preferably, (5Z,13E,9S,11R)-9,11-dihydroxy-5,13-prostadienoic acid of the formula: ##STR9## or pharmaceutically acceptable salts or lower alkyl esters is used. Among the above derivatives, a sodium salt of (5Z,13E,9S,11R)-9,11-dihydroxy-5,13-prostadienoic acid is especially preferred in the light of solubility in water.
It should be noted that (5Z,13E,9S,11R)-9,11-dihydroxy-5,13-prostadienoic acid of the formula: ##STR10## and methyl ester thereof have been described in Gorman, Proc., Natl., Acad., Sci., U.S.A. 74 vol ,9,4007-4011. However, Gorman neither describes nor suggests the use of the compounds as an intraocular pressure-reducing agent.
The carboxy moiety in the above-noted compounds may be either a free carboxylic acid or a pharmaceutically acceptable salt or ester thereof. The salt may be, for example, an alkali metal salt such as a lithium salt, a sodium salt, or a potassium salt; an alkaline earth metal salt such as a calcium salt; an ammonium salt; an organic base salt such as triethylamine, 2-aminobutane, tertbutylamine, diisopropylethylamine, n-butylmethylamine, n-butyldimethylamine, tri-n-butylamine, dicyclohexylamine, N-isopropylcyclohexylamine, tromethamine, furfurylamine, benzylamine, methylbenzylamine, dibenzylamine, N,N,-dimethylbenzylamine, 2-chlorobenzylamine, 4-methoxybenzylamine, 1-naphthylmethylamine, diphenylbenzylamine, triphenylamine, 1-naphtylamine, 1-aminoanthracene, 2-aminoanthracene, dehydroabietylamine, N-methylmorpholine or pyridine; an amino acid salt such as a lysine or arginine salt. Examples of the ester are a lower alkyl ester, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or pentyl ester. The lower alkyl ester moiety may be substituted with an optional group.
In the method of the present invention, the dose of the compounds of the formula (I) varys depending on purpose of the treatment and effect, method for administration, a particular compound used in the treatment, or age and body weight of a particular patient. Typically, in the case of oral administration, the dose is about 200 .mu.g/kg/day-about 20 mg/kg/day, preferablly about 1 mg/kg/day-about 10 mg/kg/day, but not limited to them. In the case of ophthalmic application for treating hypertension and glaucoma in the eyes, the dose is about 0.01 .mu.g/eye/day-about 1000 .mu.g/eye/day, preferablly about 0.1 .mu.g/eye/day-about 200 .mu.g/eye/day. When the compoumd of (5Z,13E,9S,11R)-9,11-dihydroxy-5,13- prostadienoic acid of the formula: ##STR11## or pharmaceutically acceptable salts or lower alkyl esters is used in the method, the preferred dose of the compound is 1 .mu.g/eye/day-about 1000 .mu.g/eye/day, and the more preferred dose is about 5 .mu.g/eye/day-about 500 .mu.g/eye/day.
The above dose which can be used in the method of the present invention may be divided into 1-5 portions in application. Accordingly, the present invention also relates to the method for treating hypertension or glaucoma in the eye comprising periodically, contacting the compounds of the formula (I) with the surface of the eye.
As another embodiment, the invention provides a kit for delivery of a solution for topical treatment of glaucoma which comprises:
(a) container having a solution including a compound of the formula (I), and PA1 (b) means for topical delivery of said solution to the eye in a controlled dosage.
Preferred kit is of the compound which is (5Z,13E,9S,11R)-9,11-dihydroxy-5,13-prostadienoic acid of the formula: ##STR12## or pharmaceutically acceptable salts or lower alkyl esters.
The compounds used in the method of the invention can be prepared by the following process:
A lactone of the formula (IV): ##STR13## in which R is hydroxy-protecting group, R.sup.2 is the same meaning as defined above is reduced with a metal hydride to form a lactol of the formula (III): ##STR14## in which R and R.sup.2 are the same meaning as above.
The resultant lactol (III) is then reacted with an ylide in the condition of Wittig reaction to yield the compound of the formula (II): ##STR15## in which R and R.sup.2 are the same meaning as above.
Following deprotection and optional esterification or salification of the compound, 15-deoxyprostaglandin derivatives of the type of PGF.sub.2.alpha. can be obtained. The hydroxy-protecting group may be selected from various protecting groups which are described in Protective Groups in Organic Synthesis, T. W. Greene, John Wiley & Sons, Inc., New York, p. 10, 1981. Examples of the protecting group are those forming an alkyl ether, such as methyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxyethyl, tetrahydropyranyl, 1-ethoxyethyl, benzyl, and p-methoxybenzyl; those forming a silyl ether, such as triethylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl; those forming an ester, such as acetyl, benzoyl, p-methylbenzoyl, and o-methoxybenzoyl.
The lactone (IV) as a starting material, is prepared from the aldehyde analogue which is obtained by oxidizing commercially available Corey lactone, using the process described below:
(i) Synthesis of compounds (IV) wherein R.sup.2 is 1-alkenyl
The compounds (IV) can be prepared by reacting the above-noted aldehyde and an ylide prepared from an alkyltriphenylphosphonium halide in the condition of Wittig reaction. If desired, cis-trans isomerization reaction may be conducted on the resultant compounds.
(ii) Synthesis of compounds (IV) wherein R.sup.2 is alkyl
The compounds (IV) can be prepared by catalytic reduction of the lactone (IV) obtained in the above process (i).
(iii) Synthesis of compounds (IV) wherein R.sup.2 is unsaturated alkyl other than 1-alkenyl.
The above aldehyde is reacted with a formylalkylenetriphenylphosphorane or an ylide obtainable from an alkyltriphenylphosphonium halide having a protected hydroxy in the condition of Wittig reaction If desired, catalytic reduction or cis-trans isomerization reaction can be conducted.
In the case that the ylide having a protected hydroxy is used, deprotection and oxidation are carried out to form formyl compounds. A desired compound (IV) can be prepared by treating the resultant aldehyde thus obtained according to the process (i).
15-Deoxyprostaglandin derivatives of the type of PGD.sub.2, PGE.sub.2, PGJ.sub.2 or PGA.sub.2 can be prepared by using the derivatives of the type of PGF.sub.2.alpha. as a starting material. The outline of the process is shown in the scheme shown below. The details are illustrated in the working examples hereinafter described. ##STR16##
The 15-deoxyprostaglandin derivatives of the invention can be administered topically or systemically using known procedures for administration. The derivatives of the invention can be formulated into a dosage form which is suitable for oral, intraarterial, intravenous, intracutaneous, intramuscular, intrarectal, or ophthalmic administration.
Recently, the inventors have found that the compounds in which the carboxy moiety is a lower alkyl ester are preferred in terms of pharmacological activity. However, esterification of the carboxylic acid results in decrease of water-solubility. Accordingly, in preparing a formulation for use as an eye drop, the compound in the form of an ester is preferably formulated into an oily formulation, or the solubility of the compound may be improved either by addition of any surfactant to the formulation or introduction of any hydrophilic group (for example hydroxy or lower alkoxy such as methoxy) into the ester moiety of the compound.
The dose of the compounds of the invention varys depending on purpose of the treatment and effect, method for administration, or age and body weight of a particular patient. Typically, in the case of oral administration, the dose is about 200 .mu.g/kg/day-about 20 mg/kg/day, preferablly about 1 mg/kg/day-about 10 mg/kg/day, but not limited to them. In the case of ophthalmic application for treating glaucoma, the dose is about 0.01 .mu.g-about 1000 .mu.g/eye/day, preferablly about 0.1 .mu.g-about 200 .mu.g/eye/day, and this dose may be divided into 1-5 portions in application.